University Of Michigan At Ann Arbor

NIH Research Projects · FY 2025 · 2025-09

Improving care for people with hypertension and diabetes in low- and middle-income countries (LMICs) is one of the most critical health challenges worldwide. Approximately 80% of people with these two diseases live in LMICs. Pharmacological management of hypertension and diabetes in primary care is one of the most highly effective and cost-effective interventions available. Yet, limited implementation of hypertension and diabetes primary care in LMICs contributes to markedly worse health outcomes than in high-income countries. The overall goal of this proposal is to evaluate the implementation of the World Health Organization’s (WHO) Hearts Technical Package (“HEARTS”) in the Ministry of Health (MOH) primary care system in Guatemala. The HEARTS model is WHO’s recommended approach to closing the “implementation gap” of hypertension and diabetes primary care in LMICs. While pilot testing in many countries shows that HEARTS is feasible, several implementation challenges have limited its population benefits. To investigate and overcome these implementation challenges, this proposal leverages a unique and time-sensitive scientific opportunity in Guatemala. In September 2024, the Guatemalan MOH is launching a fully-financed HEARTS hypertension and diabetes implementation project in 27 health districts covering >100 primary health facilities. Yet, while the implementation of HEARTS in Guatemala is fully financed, there are limited resources to evaluate its implementation. In Aim 1, the study team will conduct a mixed methods evaluation over a 30-month implementation period followed by a 30-month maintenance period. Quantitative measures will be assessed in each RE-AIM domain. Informed by quantitative results, qualitative data will be collected and analyzed to explain quantitative results. The co-primary outcomes will be in the Reach domain, defined as the count of people treated per person-month during the implementation period (“treatment rate”). The treatment rate will be calculated separately for hypertension and diabetes using a difference-in-differences approach with patient-level Ministry of Health administrative data. During the maintenance phase, RE-AIM quantitative measures will continue to be iteratively assessed, and the RE-AIM Sustainability Extension will be used to qualitatively explore the dynamic nature of sustainability, sustainability determinants, and the evolution of implementation strategies. In Aim 2, the study team will evaluate the cost-effectiveness and budget impact of HEARTS by integrating costs and clinical data into a mathematical modeling tool. This proposal leverages prior NHLBI investments in Guatemala to produce knowledge to close the implementation gap of hypertension and diabetes treatment in LMICs. The proposal is responsive to the goals of PAR-22-105 to promote implementation of evidence-based interventions into public health practice and aligns with the NHLBI’s Strategic Vision 6.CC.11: “Multidisciplinary, multinational partnerships are needed to develop effective and sustainable strategies for combating chronic HLBS disorders in developing nations.”

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Up to 16% of patients hospitalized with acute heart and lung diseases will die during their hospitalization. Mortality is up to three times higher when patients who need ICU-level care are initially triaged to a general care ward. Even after triage decisions are made, prolonged emergency department (ED) stays while awaiting an inpatient bed are increasingly common and associated with poorer outcomes for patients requiring time- sensitive or complex care. Yet, processes for ICU triage (“where should a patient be admitted”) and inpatient bed assignment (“when should they be transferred to an inpatient bed”) have failed to capitalize on modern advances in data science, causal modeling, and decision support. This results in triage and bed assignment decisions that are imprecise, impersonal, and highly variable, culminating in preventable hospital deaths. Our overall objective is to improve the care of patients with acute heart and lung diseases by developing data- driven models to support intensive care unit (ICU) triage and bed assignment. Our overall hypothesis is that personalized triage and bed assignment models can safely reduce rates of clinical deterioration and death among patients with acute heart and lung diseases. To test this hypothesis, we will complete three specific aims among patients with acute heart and lung diseases at five diverse hospitals: (1) we will identify multilevel determinants of ICU triage and bed assignment using a sequential, explanatory mixed methods study, (2) we will develop a clinical decision support model to estimate the benefit of ICU level of care for patients being admitted from the ED and evaluate it in an emulated pragmatic trial, and (3) we will develop an optimization model for inpatient bed assignment and evaluate it in an emulated pragmatic trial. Our multidisciplinary team is uniquely suited for the proposed research due to complementary expertise in data science, optimization modeling, causal inference, target trial emulation, health services research, mixed methods research, and clinical medicine. Integrating this expertise will allow us to develop innovative models guiding ICU triage and bed assignment decisions for patients with acute heart and lung diseases. We will also generate strong observational evidence of their safety and efficacy using target trial emulation, a novel way of evaluating clinical models; these results will expedite progress towards beside implementation and testing in a follow-up R01 proposal. Finally, this work will provide a framework for broader efforts to improve care delivery for patients with acute heart and lung diseases by applying innovative methods and causal inference for model development and evaluation.

NIH Research Projects · FY 2025 · 2025-09

Many weight management treatment options can support weight loss among individuals with obesity (e.g., lifestyle interventions, anti-obesity medications, bariatric surgery), but all are underutilized, and few patients (<15%) achieve and/or maintain clinically-relevant weight loss of ≥ 5%. This is due, in part, to obesity treatment barriers faced by primary care providers (PCPs) and their practices. Such barriers include (1) PCPs' lack of training in obesity medicine; (2) short clinic visits with multiple competing priorities; (3) limited capacity for frequent follow-up visits; and (4) absent strategies to proactively identify and support patients with < 5% weight loss. The overall aim of this proposal is to test a novel Weight Navigation Program (WNP) with components tailored to overcome these PCP- and practice-level barriers. Specifically, the WNP draws on principles of team-based, collaborative care and population health management to (1) enhance patients’ access to effective, preference-sensitive weight-loss treatment options through weight-focused consultation visits with obesity medicine experts, and to (2) optimize patients’ achievement of ≥ 5% weight loss through use of remote weight monitoring tools to proactively identify and support early weight loss non-responders (e.g., <3% weight loss at 12 weeks). During a 12-month pilot evaluation period, the WNP demonstrated feasibility and acceptability among patients and providers, and WNP participants (n=135) were nearly twice as likely to achieve ≥ 5% weight loss as compared to a contemporaneous matched control group from a neighboring primary care clinic. We now propose to conduct a 12-month hybrid type 1, pragmatic, randomized controlled trial to evaluate the WNP's weight loss effectiveness and implementation among primary care patients with obesity, defined as BMI ≥ 30 kg/2 (n=500). The specific aims of this study are to: (1) Compare the effectiveness of WNP versus Enhanced Usual Care (EUC) on the primary outcome of mean weight loss at 12 months; (2) Evaluate processes and determinants of successful WNP implementation using the RE-AIM framework and the Tailored Implementation of Chronic Diseases (TICD) checklist; and (3) Refine the WNP using tailored strategies that address key barriers to implementation. Key implementation outcomes include feasibility, acceptability, appropriateness, fidelity, and cost. This proposal has multiple innovations, including its use of multilevel strategies to surmount PCP- and practice-level barriers to obesity treatment, its focus on augmenting preference-sensitive use of existing obesity treatments, and its strong scientific rationale for and real-world approach to identifying and supporting early weight loss non-responders. We anticipate our WNP model will offer a scalable and sustainable approach to shift the paradigm in primary care-based weight management treatment and successfully support weight loss and improved health among patients with obesity. This directly advances NIDDK’s mission to support the research necessary to “combat the many debilitating and costly chronic diseases” and “improve people’s health and quality of life.”

NIH Research Projects · FY 2025 · 2025-09

Project Summary Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a group of major chronic inflammatory disorders of the gastrointestinal tract that affect over 3 million Americans. While genetics clearly plays a role, environmental factors, especially dietary nutrients, have been suspected of triggering disease development. Identifying the direct causal mechanisms by which genetics and dietary nutrients combine to influence IBD susceptibility may provide direct utility in uncovering both how the disease develops and how it may be treated in the future. Although genetic factors appear to play relatively minor roles in IBD, there is one particular association of single nucleotide polymorphism (SNP) that emerged at the top of a recent genome-wide association screen in IBD: a common variant in the divalent metal ion transporter SLC39A8 (p.Ala391Thr). We and others have shown that this transporter is critical for the incorporation of manganese (Mn), a micronutrient required for many enzymatic activities. These revelations hint toward alterations in Mn levels caused by diet, genetics, or a combination thereof as contributing factors for IBD. During the prior award cycle, research by our team has helped to understand how Mn, altered by diet or genetics, contributes to IBD. We provided the first evidence that dietary Mn deficiency exacerbates intestinal injury in a mouse model of IBD. We also demonstrated that SLC39A8 is not only essential for dietary Mn absorption, but also for epithelial integrity, thereby offering protection against IBD. In exploring the mechanistic drivers of Mn-induced IBD, two pivotal questions have emerged: During which developmental time stages does Mn dysregulation lead to IBD susceptibility? What are the cellular and molecular mechanisms by which low Mn levels confer a higher IBD risk with the SLC39A8 variant? This project will provide functional insight into the developmental time windows for the roles of dietary Mn and SLC39A8 gene in maintaining intestinal health, thereby advancing research into the etiology of IBD. Our findings will pave the way for future research to provide precise dietary recommendations and therapeutic interventions aimed at mitigating IBD risk across the lifespan.

NIH Research Projects · FY 2025 · 2025-09

Abstract Neonatal jaundice remains a challenge globally, contributing to significant newborn morbidity and mortality in low- and middle-income countries. This proposal, “Comparing a low-cost, hand-held icterometer to transcutaneous and serum measurement of neonatal bilirubin among dark-skinned infants: Can jaundice screening be improved in low-resource settings?” builds on previous validation research of the Bili-RulerTM, a hand-held icterometer developed at Harvard University. The Bili-Ruler has 6 digitally standardized strips of increasingly yellow hue that allow for comparison against blanched newborn skin. Previous research demonstrated acceptable diagnostic testing metrics in measuring elevated bilirubin, yet data are limited by a small sample size in patients of African descent, raising questions as to how effective the Bili-Ruler is among dark-skinned infants. We propose to conduct a robust validation study among newborns in Kumasi, Ghana, in West Africa (where 99% of the population is from one of 10 African ethnic groups) to address this gap in understanding. We aim to test the Bili-Ruler against both transcutaneous (TCB) and serum (TSB) bilirubin measurements among Ghanaian newborns to determine if this low-cost, hand-held device is a viable option to improve jaundice screening and monitoring in sub-Saharan Africa. Our study includes the following aims: Aim 1: To determine screening accuracy of the Bili-Ruler, we will compare healthcare providers’ Bili- Ruler assessments with measures of TCB on 2000 newborns and TSB on 400 newborns. We will use gestational age at birth, hours since birth, and risk factors for jaundice to determine if TCB and TSB levels are above the recommended threshold for treatment, and we will compare findings against newborns judged to have Bili-Ruler scores of 3 or higher. We will calculate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) for the Bili-Ruler against TCB and TSB. Aim 2: To determine differences in the Bili-Ruler’s accuracy based on both underlying skin tone and severity of jaundice, we will use scores on the Monk Skin Tone Scale (range: 1-10) and increasing thresholds on the Bili-Ruler (e.g. 3+, 4+, 5+) to explore differences in sensitivity, specificity, PPV, NPV and AUC for the Bili-Ruler against TCB and TSB, using healthcare providers’ assessments. Aim 3: To determine inter-rater reliability, we will compare healthcare providers’, researchers’ and mothers’ scores on the Bili-Ruler using correlation, Kappa, and McNemar’s statistical tests. This research is innovative in that it seeks to determine whether a simple, low-tech, hand-held “ruler” could be used as a valid screening tool for neonatal jaundice. If so, the implications for jaundice screening in low- resource settings is significant, given that screening could then be conducted at lower-level facilities or in remote communities without access to TCB and TSB assessments.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Associative learning is a fundamental cornerstone of behavior and cognition, but the underlying neural mechanisms remain poorly understood. In vertebrates, the inferior colliculus (IC) is a layered, midbrain hub important for sound localization, speech perception, and a potential site of plasticity for associative auditory learning. Indeed, classic studies in avians showed that neurons of the external “shell” IC layers have a substantial capacity for plasticity of auditory space maps. Additionally, early mammalian studies suggested that lesions of the analogous shell IC regions can selectively impair learned auditory associations. Interestingly, the first- and second-order targets of mammalian shell IC neurons include higher-order auditory thalamic nuclei and the amygdala, respectively; forebrain regions famously necessary for the acquisition and expression of associative learning. However, whether learning-related activity in upstream shell IC neurons contributes to these functions is less clear, owing to the difficulty of studying behaviorally relevant activity in shell IC neurons via standard techniques. We are addressing this knowledge gap using 2-photon Ca2+ imaging of shell IC neurons in behaving mice. We find that shell IC neuron activity predicts mice's behavioral choice on a trial-by- trial basis, implying substantial learning-related activity regarding the behavioral relevance of sounds. Additionally, many shell IC neurons are strongly active during trial outcomes as mice consume appetitive reinforcers. These results are exciting, as similar outcome activity is central to reinforcement learning models and provides an “instructive signal” for learning-related plasticity in many other brain regions. Given this background, we hypothesize that shell IC neurons are early plasticity loci to associate acoustic stimuli with reinforcing outcomes, thereby promoting learned instrumental responses to behaviorally relevant sounds. To test our hypothesis, we established novel cell-type specific methods to record and manipulate activity in shell IC neurons and/or their downstream targets. We propose applying these approaches as head-fixed mice learn and execute an appetitive, differential reinforcement task. The results will establish how an evolutionarily ancient midbrain circuit supports learned associations.

NIH Research Projects · FY 2025 · 2025-09

360° CHAT TMD ABSTRACT The proposed 360° Collaborative Hub for AI in TMD Research (360° CHAT-TMD) Center will establish a national, interdisciplinary, patient-centered initiative aimed at advancing temporomandibular disorder (TMD) research and improving clinical care. By uniting experts from the University of Michigan, Harvard University, and Mass General Brigham, alongside patient communities, the project seeks to bridge critical knowledge gaps in TMD and chronic overlapping pain conditions (COPCs). The collaborative focuses on four key objectives: creating an integrated computational and data science infrastructure, implementing standardized training programs, conducting interdisciplinary research to uncover TMD mechanisms, and enhancing collaboration through innovative technologies. The project is structured around two cores and two research projects. The Bioinformatics and Data Science Core (BDSC) serves as the computational and analytical hub, establishing TMD-specific common data elements (CDEs) and harmonized data integration pipelines. It leverages advanced AI/ML techniques for multi-modal disease phenotyping, fosters collaboration through secure, privacy-preserving data-sharing ecosystems, and provides biostatistical and data science expertise to study TMD subtypes, progression, and treatment outcomes. The Outreach and Training Core (OTEC) focuses on education and training, enhancing accessibility to TMD/COPCs resources for medically underserved populations and developing career development programs to mentor the next generation of clinician-scientists. Research Project 1 employs a multi-level approach to understand TMD mechanisms, using animal models to study structural changes, pain, and dysfunction, while exploring therapeutic strategies targeting pathways like hedgehog signaling and inflammation. Research Project 2 integrates AI/ML technologies for whole-person, whole-healthcare, and whole-community research. It aims to classify TMD subtypes, predict progression, and implement mobile clinical chatbots for remote outreach and patient classification. Together, these efforts align with NIDCR’s IMPACT mission and aim to transform TMD research, improve clinical care, and ultimately enhance the quality of life for patients suffering from TMD and related chronic pain conditions.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Thrombosis is a leading cause of morbidity and mortality worldwide, associated with several serious health complications including pulmonary hypertension, cardiovascular disease, and death. As thrombi mature, their structural and mechanical properties change, becoming mechanically less compliant due to fibrin crosslinking and gradual collagen deposition. The evolving mechanical properties of thrombi over time necessitates a dynamic and adaptable approach for timely diagnosis and treatment management. However, current diagnostic methods are primarily for detection of thrombi and fail to provide critical information about thrombus age and mechanical characteristics. This limitation highlights the importance of mechanistic understanding of histological (e.g., composition) and mechanical (e.g., elastic modulus) changes that occur as thrombi age, which is critical for refining treatment strategies tailored to thrombus development stage and optimizing patient outcomes. Due to the dynamic nature of thrombi and limitations of existing diagnostic methods, there is a critical need to develop a methodology for real-time quantification of evolving thrombus characteristics, such as age and elastic modulus. This will help understand the clot aging mechanism better and guide appropriate treatment selection. Our long- term goal is to develop an in situ micro-rheology technique that can non-invasively and spatiotemporally characterize aging thrombi in real-time using ultrasound responsive nanodroplets. These nanodroplets are designed to phase-transition into microbubbles when exposed to focused ultrasound above a threshold amplitude, a process known as acoustic droplet vaporization (ADV). While ADV has been utilized in several biomedical applications, such as drug delivery and super-resolution contrast imaging, its potential in micro- rheology remains unexplored. Ultrasound responsive nanodroplets can be administered intravenously and activated when they reach the thrombus site. These nanodroplets have several advantages, including their ability to form bubbles during ultrasound exposure and then rapidly recondense once the ultrasound is turned off. Additionally, their pharmacokinetic properties, such as longer circulation times due to their small size and liquid core, further enhance their effectiveness. ADV bubbles are highly sensitive to medium properties, enabling quantification of mechanical properties based on their acoustic emissions. The objective is to correlate the acoustic emissions of ADV bubbles with the mechanical properties of aging thrombi. The central hypothesis is that acoustic emissions of the ADV bubbles can be used to quantify thrombus age and elastic modulus. To test this hypothesis, we will pursue three specific aims. 1) Quantify the impact of medium properties on the acoustic emissions of ADV bubbles in thrombus-mimicking hydrogels. 2) Determine thrombus characteristics in an in vitro venous flow model. 3) Demonstrate in situ characterization of thrombus in an inferior vena cava model. The successful completion of the proposed research will be significant because it will establish a novel platform for non-invasive, real-time, and super-resolution characterization of aging thrombi.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT A wide array of evidence-based approaches is commonly used for the treatment of chronic low back pain (cLBP). Yet, most studies show that only about one third of patients with cLBP, or really any chronic pain condition, benefits appreciably from any particular treatment. Given the largely underwhelming effects of current therapies, chronic pain remains a serious public health problem and there must be a cultural transformation in how pain is understood, assessed and treated. One possible explanation for the small effect sizes seen with most of the current treatments for cLBP is that patients are not being adequately matched to appropriate interventions. Individual factors such as demographics; social determinants of health (SDOH); cognitive, affective and social factors; and especially, pain mechanisms (e.g., inflammatory, neuropathic, nociplastic) all impact the experience of pain, level of disability, and response to treatment. Thus, the critical challenge our team has been addressing for over a decade is: What treatment is best for a particular person? The need for a personalized medicine approach is at the heart of the research underway at the University of Michigan (UM) Back Pain Consortium (BACPAC) Mechanistic Research Center (MRC). To address this critical clinical challenge, our team performed an “interventional response phenotyping study” consisting of a sequential, multiple assignment, randomized trial (SMART) to evaluate treatments for cLBP from four key domains: pharmacological, physical therapy and exercise, cognitive-behavioral therapies (CBT), and mHealth pain self-management. Our preliminary data show that while about 25-30% of participants in our SMART mechanistic study respond to an assigned treatment, there are powerful predictors of treatment response that are not always intuitive. For INTERACT, we will expand on and enhance our ongoing longitudinal data collection and analysis for our unique mechanistic cohort where richly phenotyped participants undergo two treatments. First, we will enhance the data from the current UM BACPAC SMART participants by recontacting them and then collecting a more robust measurement of SDOH and early life experiences including assessment of childhood pain and trauma, as well as collecting additional follow-up data to assess long-term treatment trajectories (Aim 1). Next, we will leverage the clinical, biomechanical, MRI, performance testing, and survey data from the UM BACPAC SMART study to develop individualized phenotyping treatment rules (Aim 2) that will better match patients to treatments. We will then recruit and assess another 500 participants with cLBP and conduct a phenotype-informed SMART design study to evaluate the added benefit of matching participants to treatments using the individualized phenotyping treatment rules (Aim 3). Lastly, as the top preforming site in the BACPAC collaborative trial known as BEST, the UM INTERACT team will be enthusiastic participants in an INTERACT collaborative trial and offer ideas, infrastructure, and leadership to the network.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The pathogenesis of systemic sclerosis (SSc) is not well understood, and effective treatments are lacking. A unifying fibrosis paradigm is myofibroblast plasticity, by which quiescent resident myofibroblasts transform into activated myofibroblasts during fibrosis development. Key interactions between vascular changes and early immunological alterations occurs early in the course of disease. Loss of dermal white adipose tissue (dWAT) is another major clinical manifestation of SSc skin fibrosis. Resident mature adipocytes are lost in human and mouse skin tissues at early stage of fibrosis, yet the mechanisms that drive loss of mature adipocytes and their contribution to tissue fibrosis are unknown. In this proposal, we will examine the role of A20 in endothelial and adipocyte-specific differentiations to myofibroblasts (Endo-MT and AMT), and how attenuation of A20 in SSc patients promotes fibrosis initiation and progression, and/or retards its resolution. We will use scRNA-seq analysis to identify genes and pathways differentially regulated during Endo-MT and AMT and will correlate with SSc sc-RNA-seq dataset to examine their contribution to early stage SSc. A20 repressor DREAM by binding to A20 promoter suppress its expression. We will explore how by pharmacological/genetic approaches to increase endogenous A20 function/expression by controlling DREAM will limit adverse tissue remodeling, opening the door to novel therapeutic strategies. The project is of high impact since there are no appropriate treatments for SSc. Moreover, the results will have a strong impact on myriad fibrosing diseases that currently lack effective treatment.

NIH Research Projects · FY 2025 · 2025-09

Abstract Exercise is an important modulator of human health, and mechanical loading during strength and resistance- based exercise is well known to positively impact bone mass by enhancing osteoblast-mediated bone formation. However, there is a fundamental gap in understanding the response of bone to aerobic metabolic demands found in activities like running and cycling, and how those demands interact with the mechanical loads placed on the skeleton during exercise to differentially modulate bone mass. Emerging evidence shows that aerobic exercise induces acute elevations in the bone resorption marker carboxy-terminal telopeptide of type I collagen (CTX) without compensatory changes in bone formation, suggesting an immediate and unexplained pro-resorptive response. While well-documented, there is substantial lack of prior rigor regarding the cell source, extent, and purpose of elevated bone resorption during aerobic exercise. These questions are important because they may help facilitate the development of more precise recommendations for aerobic exercise to modulate bone health. Furthermore, they may provide greater understanding of factors governing bone loss in conditions of high metabolic demands or low energy availability that often result in fractures or additional disability in vulnerable populations. The central hypotheses of this proposal are that the source of CTX elevation during exercise exists on a spectrum between osteocyte perilacunar remodeling (PLR) and osteoclast resorption, the extent of which is governed by energy demands during exercise, and that CTX elevation is proportional to amino acid flux into skeletal muscle. These hypotheses will be tested in three distinct, non-overlapping specific aims. Aim 1 will determine the source of elevated CTX during aerobic exercise. We will selectively inhibit osteocyte perilacunar remodeling using MMP13ocy-/- mice and compare exercise-induced elevations in CTX to mice treated with pamidronate, which we have previously shown can inhibit osteoclast activity in the face of sustained PLR, or cathepsin K inhibitor, which selectively inhibits collagen degradation, but not demineralization of the bone ECM. Aim 2 will determine the relationship between CTX elevation and energy demands during exercise. We will run well-trained human subjects, and rats bred for high and low aerobic capacity, at treadmill speeds correlating with varying oxidative and non-oxidative energy demands. Subjects will run on commercial (human) and custom (rat) treadmill-interface systems to uncouple metabolic demands from biomechanical loading, and we will further modulate energy demands in the presence or absence of carbohydrate supplementation. Lastly, Aim 3 will evaluate the relationship between CTX elevation and amino acid distribution to skeletal muscle during aerobic exercise. We will assay circulating and muscle-targeted amino acids in rodent samples to quantify amino acid flux to the muscle in relation to both modulation of bone turnover and energy demands of the exercise itself.

NIH Research Projects · FY 2025 · 2025-09

State-dependent gating of memory and plasticity in the aging brain Memory loss and sleep disturbances are among the most prevalent and debilitating health concerns in the aging population. Together they threaten the independence and quality of life of older adults and their families, costing the healthcare system over $800 billion worldwide. The long-term objective of this project is to understand the link between sleep disturbances and memory problems that arise during aging. Growing evidence suggests that sleep disturbances are a mediator of age-related memory problems. Previous work shows that sleep deprivation (SD) hampers memory function in animal models, and reduces the activity and connections of principal neurons in the hippocampus—a brain region crucial for memory processing. In addition, recent data show that SD increases the activity and connections of somatostatin-expressing (SST+) inhibitory interneurons. By altering the activity of SST+ cells, the hippocampal excitatory/inhibitory (E/I) balance shifts to a state incompatible with memory storage. E/I imbalance is also observed with aging. Nevertheless, how aging alters E/I balance to disrupt memory is still unknown. The overall objective of the current research is to test the hypothesis that sleep disturbances in aging result in memory impairments via effects on the function of SST+ interneurons. The central hypothesis is that age-related sleep disturbances alter the activity and/or connectivity of hippocampal SST+ interneurons, shifting the E/I balance, and causing memory problems. Using Brainbow labeling and patch- sequencing, Aim 1 will quantify the structure, function, and gene expression of hippocampal SST+ cells in aged versus adult mice, and test whether partial chronic SD or a sleep-promoting hypnotic treatment can worsen or rescue phenotypes associated with aging, respectively. From a training perspective, Aim 1 will facilitate development of new experimental and analytical skills, including collecting, analyzing, and modeling transcriptome data using bioinformatics. Aim 1 will also expand my conceptual background in the domain of aging, with opportunities to improve my science communication, mentoring, and grant writing skills. The mentoring team, composed of experts in the field of cognitive aging, bioinformatics, and sleep neurobiology, will facilitate these aspects of my career development at the University of Michigan, which is one of the world's leading research universities. During the independent phase, Aim 2 will assess how aging affects the cell type- specific transcriptome landscape with respect to memory function—using spatial transcriptomics—under conditions of ad lib, chronically disrupted, or hypnotic-augmented sleep. This analysis will provide greater insight into how aging and sleep affect biological pathways, including neuronal and glial cellular function. Together, the proposed research is the first to directly assess the relationship between sleep, memory, and E/I balance in the context of aging. Understanding how age-related sleep disturbances affect memory-processing brain circuits will lead to the development of new therapeutic strategies to mitigate or even prevent age-related cognitive decline.

NIH Research Projects · FY 2025 · 2025-09

High intensity drinking (HID; consuming 8+ standard drinks for women and 10+ for men) is most common among emerging adults (EAs), reflecting an important public health concern and NIAAA priority. HID increases risk for deleterious outcomes in the short and long-term (e.g., development of alcohol use disorders [AUD]). Experts have called for novel approaches tailored for people engaged in HID, with a key innovation proposed herein being to harness social media interactions given that EAs use these platforms frequently. Our team used iterative participatory methods to develop and pilot the first intervention for EAs engaged in HID. Given EA norms of daily social media use and the potential for social media to reach beyond clinical and school settings for intervention delivery, we used private social media 1:1 messaging with health coaches to deliver 8-weeks of motivational interviewing-based theoretically-derived interactive content. Pilot data supported intervention acceptability (e.g., 85% liked messaging) and trial methods were feasible (e.g., enrollment targets met, 92% intervention engagement, >=88% retention at 4-months). Descriptive results showed promise for alcohol outcomes at the 4-month follow-up (2-months post-intervention end) such as typical weekly drinking (Cohen’s d=.31) and alcohol use severity (AUDIT-C d=.28). Beyond alcohol, intervention content focused on stress, coping with negative affect, and promoting mental health, showing promise for depression (d=.40) and anxiety (d=.38) outcomes. Given these results, we propose a fully-powered randomized controlled trial, with an EA advisory board, to evaluate the short- and long-term efficacy of this innovative intervention in comparison to a control condition over 12 months of follow-up. Aim 1 will involve efficacy testing with the primary outcome of typical weekly drinking (reflecting overall consumption), with secondary (e.g., AUDIT-C score, depression and anxiety symptoms) and exploratory outcomes (e.g., quality of life, drug use) also evaluated. Aim 2 will employ novel machine-learning data mining techniques using participant data (e.g., demographics etc.) combined with community-level data (e.g., Census data) to identify characteristics of individuals who show positive responses, guiding future implementation of personalized medicine approaches. Moderators and mediators will also be explored. Interventions that harness social media to deliver support from health coaches in EAs’ daily lives are scalable and can be easily tailored by coaches in the moment to changing individual needs, trends and contexts of alcohol use, improving upon high-resource, static electronic interventions with limited shelf-life by allowing for a wide reach unconstrained by setting. Key innovations include ushering in a new method of health coach intervention delivery for EAs engaged in HID, holistically addressing mental health as intertwined with HID, and using machine learning analyses to evaluate predictors of response. There is potential for significant public health impact by reducing risky drinking and related consequences and preventing AUD onset in EAs.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT Older adults living with Alzheimer’s disease and related dementias (ADRD) experience remarkably complex care transitions after hospitalization. Over half have medication problems (e.g., errors, discrepancies, inappropriate use), increased care partner burden, health-related (e.g., behavioral symptoms), and social needs after the care transition home. Our team has a sustained evidence-based care transition program for rural older adults, the Region VII Area Agency on Aging Community Care Transition Initiative (CCTI), including a community health worker (CHW) home visit and telehealth pharmacist medication review that addresses medication discrepancies and optimization, social and health-related needs, provides referrals and follow-up. Gaps in our knowledge of individual and organizational determinants to inform effective adaptations for rural older adults with ADRD and their care partners and successful implementation interventions appropriate for rural Area Agencies on Aging exist. The overall objective is to identify the key factors for adapting the CCTI for rural older adults with ADRD and their care partners (i.e., CCTI-ADRD) and to test the feasibility and acceptability of implementing the adapted CCTI-ADRD. The Tailored Implementation in Chronic Disease (TICD) framework informs our aims. AIM 1: Determine factors for adapting and implementing the Community Care Transition Initiative-ADRD to address medication problems, care partner burden, and health and social needs of rural older adults with ADRD and their care partners. We will conduct semi-structured interviews and direct observations with key informants (those with ADRD and their care partners, CHWs, Area Agency on Aging staff, and healthcare providers) and use rapid qualitative analysis and the TICD framework to prioritize factors, critical adaptations, and implementation barriers and facilitators. With our community advisory board, comprised of older adults with ADRD and their care partners, pharmacists, CHWs, and Area Agency on Aging members, we will reach a consensus on our implementation toolkit and pilot study protocol. AIM 2: Test the feasibility and acceptability of implementing the Community Care Transition Initiative-ADRD in three rural Area Agencies on Aging. Using a mixed-methods implementation pilot study, we will assess our primary outcomes of feasibility and acceptability of the implementation strategies. Secondary outcomes are implementation fidelity, medication problems addressed, care partner burden, ADRD behavioral symptoms, and community- based services provided. Direct observations, surveys, chart reviews, and semi-structured interviews with key informants will be used. We will integrate our data, create a causal pathway diagram to examine why our implementation strategies worked, and refine our toolkit. The expected outcome is our tailored implementation toolkit to be tested further in a randomized hybrid effectiveness-implementation clinical trial. We will positively impact rural older adults with ADRD and their care partners by reducing medication problems and unmet social and health needs after the care transition home.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Severe RSV-bronchiolitis infection has been associated with the development of asthma later in childhood. RSV is the primary cause of bronchiolitis in children worldwide, and it is considered the most impactful risk factor for asthma development among causative pathogens. The therapeutic options are limited. The mechanism by which early-life RSV (EL-RSV) infection predisposes to asthma later in life is unknown. Our studies will investigate the mechanism behind asthma development after EL-RSV infection by focusing on long- term lung epithelial cell alterations generated by epigenetic modification. We will specifically investigate the role of the innate cytokines IL-1β and IL-33 in long-term lung epithelial alteration since we had observed these cytokines highly upregulated during RSV infection. The present proposal provides preliminary data demonstrating that EL-RSV infection generates long-term phenotypic changes in the alveolar epithelial cell type II (AT2) through epigenetic modification in the Il33 gene promoter. These phenotypic changes in the lung epithelium after EL-RSV infection likely modify airway allergic reactions later in life. Additionally, we have identified changes in the ratio of AT2:AT1 cells and altered pulmonary function, suggesting that EL-RSV infection may generate aberrant lung development or repair. Therefore, we will address our hypothesis that EL-RSV infection generates long-lasting lung epithelium alterations that impact lung reactivity to allergens. This leads to the upregulation of innate immune mediators, such as IL-33, that increase the risk of developing respiratory allergies later in life. This hypothesis will be tested by the following specific aims: Aim 1- To determine the acute and persistent mediators and activated pathways responsible for inducing long-term alterations in the lung following EL-RSV infection. We hypothesize that EL-RSV causes long-lasting changes in the lung epithelium, leading to lung functional and structural changes and predisposition to lung pathologies later in life. Aim 2- To investigate the mechanisms underlying long-term changes in the lung epithelium after EL- RSV infection by focusing on the RSV-related immune mediators IL-1β and IL-33. We hypothesize that RSV-related immune mediators IL-1β and IL-33 are critical in generating long-term alteration of the lung epithelial cells. Aim 3- To determine if RSV infection generates epigenetic modifications in the lung epithelial cells that define the long-term alterations in the lung epithelium that contribute to the development of asthma. We hypothesize that EL-RSV infection drives long-term alteration of lung epithelial cells by modifying the chromatin organization and accessibility across the genome through histone modification.

NIH Research Projects · FY 2025 · 2025-09

There are millions of people worldwide with debilitating upper limb amputations. While electrical signals from residual muscle can provide some function, every person with amputation is missing muscles, and therefore missing a variety of important functions. Our group has demonstrated a novel method for obtaining signals from independent nerve fascicles in humans, which we call the Regenerative Peripheral Nerve Interface (RPNI). The small muscle grafts degenerate, regenerate, revascularize, and reinnervate utilizing natural biologic processes. Our long-term goal is to make nerve-controlled prostheses widely available, such that multi-articulated hands can be controlled as dexterously and intuitively as an anatomic limb. The objective of the present application, which represents our proposed next step, is to obtain the necessary regulatory approvals to conduct a pilot take- home clinical trial of a portable control system for recording intramuscular signals from RPNIs and residual muscles in 6 participants with upper limb loss. In the UG3 portion of the study, we will address the following aim: Aim 1. Enable advanced prosthetic functionality using a small wearable device to process RPNI signals. In the UH3 portion of the study, we will address the following aims: Aim 2. Determine whether intramuscular EMG with RPNI signals can reliably and intuitively improve activities of daily living. and Aim 3. Compare prosthetic use and function during take-home trials of prosthetic controllers using surface pattern recognition and those using pattern recognition of intramuscular electromyography from residual muscles and RPNIs. We have partnered with industry (Ossur, Synapse Biomedical, Blue Arbor Technologies) to ensure the system we develop will be safe and manufacturable in the future. We believe successful completion of these aims will motivate commercialization and widespread use of RPNIs for prosthetic control.

NIH Research Projects · FY 2025 · 2025-09

Sepsis and its consequences such as organ dysfunction and failure remain significant human health problems. We have identified blood metabolites (small molecular weight compounds) including a by-product of mitochondrial fatty acid β-oxidation, acetylcarnitine (C2), that are associated with sepsis-induced organ dysfunction and mortality. Additional preliminary data suggest that blood levels of C2 during sepsis is associated with single nucleotide polymorphisms (SNPs) in the OCTN2 gene (SLC22A5; rs2631367,- 207C>G), the transporter that shuttles C2 out of cells. A SNP that is inconsequential in health, this gene and several master metabolic regulator genes may have biological relevance in disease. Furthering understanding of the associations between genetic variants and sepsis metabolite levels will bring insights to the mechanisms that enhance or attenuate sepsis severity (organ dysfunction) and mortality as well as aid in identifying drug target opportunities. Using the BioLINCC R21 mechanism we propose to conduct a preliminary metabolomics- genome-wide association study (GWAS) by leveraging DNA and plasma biospecimens from The Crystalloid Liberal Or Vasopressor Early Resuscitation in Sepsis (CLOVERS) trial. We will use the requested BioLINCC stored plasma and paired DNA specimens from 600 CLOVERS participants to generate metabolomics and GWAS data, respectively. We will test the central hypothesis that master metabolic regulator gene SNPs are associated with metabolite blood levels that contribute to sepsis-induced organ dysfunction and mortality via the following aims: Aim 1: Identify the genomic and patient level-factors that contribute to acetylcarnitine blood levels in patients with sepsis. We will test associations between 114 SNPs of metabolic regulation, fatty acid β-oxidation, and acylcarnitine transport and acetylcarnitine blood levels. Our working hypothesis is that SNPs in genes involved in the regulation of fatty acid β-oxidation and the transport of acylcarnitines contribute to the broad dynamic range of acetylcarnitine blood levels in patients with sepsis. Aim 2: Determine genetic associations of differentiating metabolites of sepsis-induced organ dysfunction. We will use our entire metabolomics data set which covers a broad range of different classes of metabolites, many of which are expected to be associated with organ function. Using the wealth of genomic data from the GWAS, we will test associations between each SNP and each differentiating metabolite. Our working hypothesis is that there are genetic variant-metabolite associations that contribute to sepsis severity. We expect to identify 1) SNPs associated with sepsis-induced increases in acetylcarnitine levels and 2) additional genetic variant-metabolite associations linked to sepsis outcomes. Collectively, this work will advance understanding of molecular mechanisms that underlie sepsis-induced amplification or attenuation of metabolic processes that contribute to sepsis. The findings will also generate testable hypotheses for planned future R01 applications that will use the entire CLOVERS cohort to generate whole genome sequencing and temporal metabolomics data.

NIH Research Projects · FY 2025 · 2025-09

Metabolic dysfunction-associated steatotic liver disease (MASLD), is caused by excess accumulation of fat in the liver (steatosis), has a global prevalence of 25.2% and is becoming the most common cause of chronic liver disease worldwide. MASLD prevalence varies across ancestries with individuals of Hispanic ancestry having a higher prevalence (34–58%) than European (28–45%) and African (19–35%) ancestry individuals. There are few effective ways to prevent or treat MASLD making it one of the biggest unmet medical and public health needs of our time. MASLD is heritable or genetically influenced and thus its causes can be uncovered using genetic analyses. While histology has historically been used to define MASLD, we pioneered the use of Computed Tomography (CT) based imaging based hepatic steatosis measurement to define MASLD in the Framingham Heart Study and used this across population-based cohorts to identify genetic variants that reproducibly associated with MASLD. We combined CT with Magnetic Resonance Imaging based hepatic steatosis as well as ICD measured MASLD across many cohorts to identify genetic variants that associate with MASLD at genome wide significant levels in the most powered genetic analyses of this trait. Trans ethnic analyses of implicated loci confirmed that these variants had effects on MASLD across ancestries. In separate analyses we identified ancestry specific alleles in MASLD implicated genes suggesting novel disease promoting loci may exist in non- European populations. We have knocked out or overexpressed candidate associated genes in liver cell lines where we can verify an effect on affecting hepatic steatosis or other liver phenotypes. Since known variation explains only 20% of the heritability of MASLD additional genetic loci that predispose to MASLD remain to be discovered. To overcome previous limitations of using imputed genetic data and mostly European ancestry samples here we aim to identify additional common and rare variants with effects on MASLD through whole genome sequencing (WGS) in large ethnically diverse populations. Implicated genes from these analyses will be functionally tested for effects on hepatic steatosis to confirm causality using library based CRISPR/cas9 screening. Results from this work will to improve the diagnosis, management, treatment and ultimately prevention of MASLD by understanding the genomic contributions to its pathophysiology.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT Deaf and hard of hearing (DHH) women are at substantially higher risk of adverse birth outcomes and severe maternal morbidity and mortality (SMMM), a composite measure of 21 indicators of life-threatening pregnancy-related health problems, compared to non-DHH populations. Preliminary data indicate DHH-Black pregnant women may be at even further elevated risk of SMMM compared to white non-disabled pregnant women, which suggests intersectional axes, the overlapping of social identities that interact and may compound SMMM risk. Obstetrical toolkits that bundle evidenced based practices are one approach to address disparities, but none are tailored to specific patient populations, suggesting an urgent gap in care. The study objectives are to identify the leading SMMM indicators of DHH and DHH-Black intersectional disparities and develop a patient-informed obstetrical toolkit with the long-term goal of improving SMMM. We hypothesize that the leading clinical indicators for SMMM will be distinct in DHH and DHH-Black women compared to non-DHH/non-Black women, and DHH-Black women will have compounded risk and higher burdens of comorbidities, social determinants of health and inadequate prenatal care. The specific aims are to: 1a) Compare the clinical indicators for SMMM, and test how health system factors such as obstetric comorbidity scores, social determinants of health, and the prenatal care adequacy contribute to SMMM in DHH and DHH-Black compared to non-DHH/non-Black cohorts nationally; 1b) Use linked longitudinal claims data from Massachusetts and South Carolina to compare DHH and DHH-Black compared to non-DHH/non-Black women’s risk of SMMM, the timing of greatest vulnerability in the perinatal period, hospital facility factors, and healthcare utilization (readmissions and visits) from pregnancy to one year postpartum; 2) Gain patient perspectives of Aim 1 health system and clinician factors that contribute to SMMM; and 3) Develop a toolkit informed by Aims 1 and 2 results. The expected outcomes are much needed epidemiologic evidence on the leading indicators and contributors of SMMM in DHH women and a patient-informed obstetrical toolkit to reduce SMMM with future potential for adaptation to other populations.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Breathing disorders affect most individuals with obesity—and while respiratory muscle dysfunction occurs with elevated BMI, its underlying pathophysiology and potential therapeutic targeting in obesity-associated pulmonary compromise are largely uninvestigated. Mice subjected to diet-induced obesity (DIO), develop diaphragm weakness. In these animals, intra-diaphragmatic adiposity, and extracellular matrix (ECM) content quantitatively correlate with reductions in muscle contractile force. Resident mesenchymal cells called fibro-adipogenic progenitors (FAPs) are the source of all adipocytes and many ECM-depositing cells in the obese diaphragm. With DIO, diaphragm FAPs assume a proliferative, fibrogenic phenotype, and differentiate toward a Thy1- expressing sub-population previously linked to muscle degeneration. Thrombospondin-1 (THBS-1) is a matricellular protein produced by cell types including macrophages, adipocytes and FAPs. Physiologically induced by injury and ischemia, THBS1 levels chronically increase in obesity. A FAP mitogen and activator of TGF signaling, THBS-1 has been linked to fibrotic and degenerative changes in genetic myopathies. Global Thbs1 knockout subjected to DIO gain equivalent weight to WT controls, but do not exhibit FAP pool expansion or shift toward the Thy-1 expressing sub-type. Moreover, Thbs1-null diaphragms are protected from obesity-induced increases in adiposity and ECM deposition. Strikingly, Thbs1 knockout mice maintain normal diaphragm contractile force and motion with DIO. We hypothesize mesenchymal THBS1 promotes TGF-mediated, FAP-driven stromal expansion that can be targeted to mitigate diaphragm weakness and respiratory dysfunction in obesity. We will test the hypothesis through cell and tissue-based systems, in genetically engineered mouse models, and in human subjects: (1) First, we will employ primary cell culture to interrogate TGF and other putative THBS1 effectors as drivers of FAP proliferation, fibrogenesis and adipogenesis. We will then leverage a FAP-myobundle organoid system to determine whether the negative impact of THBS1 on muscle contractile function depends on FAPs. (2) Next, we will apply mouse models of inducible cell type-specific Thbs1 ablation (macrophage, adipocyte, FAP) to establish the cellular source of pathogenic THBS1 in obesity. We will also treat DIO mice with agents targeting THBS1/TGF-driven fibrosis to test whether this maneuver is sufficient to forestall or reverse pathological diaphragm remodeling and respiratory dysfunction. (3) Finally, we will analyze a translational weight loss cohort to define the relationship among circulating THBS1 levels, diaphragm motion (ultrasound measurement of diaphragm excursion amplitude), and diaphragm fibro-adipogenic remodeling (ultrasound measurement of muscle echo intensity). Together, the proposed experiments will define targetable cellular and molecular mechanisms underlying obesity-induced respiratory dysfunction.

NIH Research Projects · FY 2025 · 2025-09

Despite almost all postpartum women wanting to delay their next pregnancy by at least two years, contraceptive use remains inconsistent, particularly in Ghana, which has one of the highest levels of unmet needs for family planning in sub-Saharan Africa. Prior research has shown the quality of contraceptive care in Ghana is poor, with many women adopting methods known to cause side effects women indicated were unacceptable to them. Contraception is a preference-sensitive health service; there are often multiple medically appropriate options available to women, and so their own preferences ought to drive the decision of whether or not to use contraception, and if so, which method. Increasing client autonomy has been recognized as the next frontier in improving the quality of contraceptive care women receive. In this project, our longstanding collaborative, cross-national, interdisciplinary team will tailor an mhealth intervention to postpartum women and follow them for two years post-delivery to determine the impact of the tablet-computer based decision-support tool on contraceptive autonomy, maternal mental and physical health, and health of the index baby. This study, conducted by a collaborative team from the University of Michigan and the Kwame Nkrumah University in Ghana, aims to improve the understanding and usage of postpartum contraceptives and the impacts of using My Family Planning-Ghana (MFPG), an adaptation of a US-based decision-support tool. To achieve this, the project focuses on three objectives. The first aim is to adapt MFPG for postpartum women, including those undecided about contraception, using the ADAPTITT framework. By testing the tool in postnatal and child welfare clinics, our goal is to make the tool feasible, acceptable, and sensitive to the needs of postpartum women. In the second aim, we will assess the tool's impact on contraceptive behavior through a cluster-randomized controlled trial. This study will enroll pregnant women in their third trimester and follow them for twenty-four months to determine whether the tool increases contraceptive autonomy, access to preferred methods, and selection of methods that meet users’ preferences. It will also assess the tool's impact on birth spacing, pregnancy outcomes, maternal health, and contraceptive autonomy over a two-year period. The third aim will examine whether using the decision-support tool is associated with improved health outcomes and resource investment for infants and children. The study will assess whether children of women in the intervention group have superior nutritional status, growth, health, breastfeeding duration, and healthcare usage compared to those in control group. This project provides an opportunity to improve contraceptive autonomy in the postpartum period, a global issue of which poor quality contraceptive care is a significant part. The intervention seeks to empower women to use contraception that meets their preferences if they want to and assists in achieving their fertility goals and healthy birth spacing, and could be adapted for use in other countries, including the United States. The research team combines expertise and exceptional research infrastructure to conduct a feasible, rigorous study of a tool with potential for high impact.

NIH Research Projects · FY 2025 · 2025-09

Adults with elevated clinical risk factors experience nearly double the prevalence of type 2 diabetes (T2D) and increased mortality from related complications compared to the general population. Once diagnosed, these individuals often demonstrate suboptimal glycemic management, leading to heightened risk of adverse outcomes. Our previous work indicates that behavioral norms and self-reliance expectations may limit care-seeking behaviors and reduce adherence to clinical recommendations, thereby compromising diabetes management. This evidence suggests that diabetes self-management support (DSMS) interventions must be adapted to reflect the behavioral profiles, health system engagement patterns, and logistical constraints common among these individuals to be effective. However, many PLDSMS studies have enrolled participants whose clinical profiles and healthcare utilization patterns differ from the populations most affected by suboptimal management, limiting generalizability. To address this gap, our team used two pilot grants to develop and deliver a virtually administered, evidence-based PLDSMS protocol tailored for logistical feasibility and real-world implementation. These pilots, MDP I and MDP II, demonstrated improvements in A1C, dietary behavior, self-monitoring, and reductions in diabetes-related distress. They also showed that PLs can deliver this model with fidelity in virtual settings and that the approach is both usable and well-received, with an average recruitment and retention rate of 80%. The objective of our proposed study is to conduct a two-arm, Hybrid Type 1 effectiveness-implementation trial comparing the adapted PLDSMS with enhanced usual care (EUC) among adults with T2D and elevated clinical risk. Specifically, we will: (1) collaborate with a Clinical, Administrative, and Research Advisory Board (CARAB) to optimize implementation for scalability; (2) evaluate PLDSMS impact on A1C, diabetes-related distress, and T2D self-management behaviors relative to EUC; and (3) conduct a comprehensive evaluation of implementation outcomes including acceptability, feasibility, and cost-effectiveness within the Detroit Health Department (DHD). The PRISM framework and the Design for Dissemination and Sustainability (D4DS) Planner will be used to guide implementation analysis and sustainability planning. This study will: a) validate the effectiveness of an empirically adapted, evidence-based DSMS model in a pragmatic public health setting; b) generate insights on the integration of PLDSMS into existing clinical and public health infrastructures; and c) inform future large-scale dissemination of structured, peer-delivered support models aligned with NIDDK’s goal to advance science-based strategies for T2D management and prevention.

NIH Research Projects · FY 2025 · 2025-09

The goal of the new Michigan Emergency Medicine Physician-Scientist StARR Training Program is to enhance research training and career development opportunities for emergency medicine (EM) resident investigators at the University of Michigan. The program will recruit and train outstanding resident investigators in research related to heart, lung, blood, and sleep (HLBS) disorders and biological systems, across areas of basic, clinical, translational, and health services research. There is a significant need for additional research training in EM, and one clear gap is the lack of dedicated research training programs for EM residents. To successfully conduct high-quality research, obtain research funding, and launch a research career, physician-scientists need a period of targeted training and mentoring with appropriate dedicated research time. This program aims to provide these key opportunities for EM residents committed to pursuing academic careers as physician-scientists. The program will be housed in one of the leading academic EM departments nationally, and it will be led by expert EM researchers and educators. The program also includes a group of over 20 highly qualified faculty who will serve as mentors, all with productive, well-funded HLBS research programs and a demonstrated track record of commitment to trainee research skill development. The program aims include the following: 1) Recruit and train EM resident investigators in HLBS research. The program will support 2 outstanding EM resident trainees annually, allowing residents to complete 12 additional months of research training. 2) Develop a competency-based, flexible training program that utilizes evidence-based best practices to maximize the likelihood of EM resident-investigator success. Each resident will work with their mentorship team to create an individualized development plan and pursue training in rigorous medical research, scientific and grant writing skills, and leadership skills. 3) Develop and maintain a robust evaluation system for learners and the program, enabling continuous program improvement, and ensuring trainees become highly competitive K award applicants. Program evaluation will include monitoring actionable metrics, soliciting active trainee and mentor feedback, and tracking post-program trainee career success. This will be achieved through a flexible program that engages potential resident-investigators at all levels of research experience. Overall, the proposed StARR program will provide EM residents with the skills necessary to enter their post-residency positions in an advanced state of preparedness and will accelerate their time to an independent research career. The program is designed to increase the number of EM physician-scientists conducting HLBS research.

NIH Research Projects · FY 2025 · 2025-09

Overall Abstract: Fragile X-associated Conditions (FXaCs) are a heterogeneous group of disorders arising from alterations in the size and epigenetic state of a polymorphic CGG repeat within FMR1. Described as the first repeat expansion disorder over 30 years ago, FMR1 CGG repeat expansions cause neurological, reproductive, and neurodevelopmental diseases while also serving as an archetype for understanding repeat expansions and the mechanisms by which they elicit dysfunction. Work over decades delineated the native functions of the fragile X protein, FMRP, and the consequences of its loss and identified toxic gain-of-function mechanisms (DNA toxicity induced by R-loop formation, RNA toxicity mediated by protein sequestration, and protein mediated toxicity from Repeat associated non-AUG (RAN) translation) elicited by transcribed CGG repeats. Despite these advances, we lack effective therapies for any FXaC – at least in part due to the enigmatic clinical heterogeneity and incomplete penetrance of FxaCs that confound targeted approaches. Here we propose a change in our approach to FXaCs. Rather than focusing solely on specific diseases (Fragile X Syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), or fragile X-associated primary ovarian insufficiency (FXPOI)), the Center structure enables us to directly engage the mechanistic crosstalk between conditions and between the FMR1 locus and related repeat expansion disorders. Our central hypothesis is that a deeper understanding of genetic, pathologic, and environmental factors which underlie the variable clinical manifestations of premutation (PM)-associated disorders will reveal novel insights into both how repeats cause disease and how we can target them therapeutically. We will address this hypothesis in three highly integrated projects all focused on premutation disorders. These projects will use data-driven genomic and bioinformatics approaches coupled with emerging tools and multiple model systems. Our outstanding team of experts from four leading sites of Fragile X research features both junior and senior investigators and runs the gamut from clinicians to neuroscientists to geneticists to reproductive biology experts. By pooling our substantial data, expertise and resources, we will pursue identification of novel pathogenic mechanisms in FX premutation disorders and develop a series of robust and viable targets and approaches for therapeutic development in FXaCs.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or meaningful treat- ments. ALS is mostly sporadic, and for most, evidence supports a gene-time-environment hypothesis of ALS triggered by a confluence of nonmodifiable risk factors (age, sex, and genetics) and modifiable risk factors from the exposome (a person’s cumulative lifetime exposures). Exposures imprint on the epigenome via DNA meth- ylation (DNAm) marks, which change with age, modifying cellular response to environmental insults. Compre- hensive knowledge of all these factors is needed to develop personalized prevention strategies for those at highest risk and personalized therapeutics for those already living with ALS. We reported that biofluid- and sur- vey-based exposure measures, summarized by environmental risk scores (ERS), strongly impact ALS risk and progression, adjusted for genetic background. We also recently discovered that epigenetic age acceleration, calculated from DNAm, is associated with ALS risk and exposures. However, the full spectrum of nonmodifia- ble and modifiable risk factors resulting changes in the epigenome are incompletely characterized. There is a critical need to fill this gap and determine how these factors impact ALS risk and the epigenome, leading to a better understanding of disease etiology, which can inform future precision strategies to prevent ALS. Our long-term goal is to leverage knowledge of the ALS exposome to inform personalized ALS prevention and therapeutic strategies. Our current objectives are to (i) comprehensively assess the exposome in our Michigan cohort and determine how it associates with ALS risk and survival; and (ii) gain insight into disease etiology by examining the intersection of the exposome with the ALS epigenome and transcriptome. Our central hypothe- sis is that ALS cases will have higher ERS scores, which correlate with epigenetic and transcriptomic changes and ALS risk and survival. In Aim 1, we will leverage targeted and untargeted exposomics in biofluids to identi- fy toxicant exposures that associate with ALS risk and survival and determine the effects of age, sex, and pol- ygenic risk on these outcomes. In Aim 2, we will identify geospatial- and survey-based exposomic measures linked to ALS risk and survival, and evaluate how they associate age, sex, polygenic risk, and biofluid toxicant measures. Finally, in Aim 3, we will characterize exposome-related DNAm and transcriptomic signatures and their association to ALS risk and survival. Completion of these studies will identify ALS-relevant exposome fac- tors that associate with to disease risk and survival via DNAm and consequent transcriptomic changes. These results will have important translational impact by lending insight into ALS etiology and identifying exposomic factors that most impact ALS risk and survival, thereby making the first critical steps towards personalized risk prediction and prevention strategies in ALS by exposure mitigation.